Development of potent and selective tetrahydro-β-carboline-based HDAC6 inhibitors with promising activity against triple-negative breast cancer

  • RSC Med Chem. 2025 Apr 17. doi: 10.1039/d5md00086f.
Aya Fathy  1 ,  Amro Allam  1 ,  Ahmed K ElHady  1  2 ,  Dalia S El-Gamil  1  3 ,  Kai-Chun Lin  4 ,  Yen-Hua Chang  4 ,  Yu-Hsuan Lee  5 ,  Sebastian Hilscher  6 ,  Mike Schutkowski  6 ,  Hany S Ibrahim  6 ,  Shun-Hua Chen  7 ,  Chun-Hong Chen  8 ,  Ashraf H Abadi  1 ,  Wolfgang Sippl  6 ,  Po-Jen Chen  8  9 ,  Yi-Sheng Cheng  4  5  10 ,  Mohammad Abdel-Halim  1
Affiliations
  • 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo Cairo 11835 Egypt [email protected].
  • 2. School of Life & Medical Sciences, University of Hertfordshire hosted by Global Academic Foundation New Administrative Capital Cairo Egypt.
  • 3. Department of Chemistry, Faculty of Pharmacy, Ahram Canadian University Cairo 12451 Egypt.
  • 4. Institute of Plant Biology, College of Life Science, National Taiwan University Taipei 10617 Taiwan.
  • 5. Department of Life Science, College of Life Science, National Taiwan University Taipei 10617 Taiwan.
  • 6. Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg Halle (Saale) Germany.
  • 7. School of Nursing, Fooyin University Kaohsiung 831301 Taiwan.
  • 8. Department of Medical Research, E-Da Hospital and Graduate Institute of Medicine, I-Shou University Kaohsiung 824410 Taiwan [email protected].
  • 9. Department of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University Kaohsiung 80708 Taiwan.
  • 10. Genome and Systems Biology Degree Program, College of Life Science, National Taiwan University Taipei 10617 Taiwan.
PMID: 40256307 DOI: 10.1039/d5md00086f
Abstract

Overexpression of histone deacetylase 6 (HDAC6) is implicated in tumorigenesis, invasion, migration, survival, Apoptosis, and growth of various malignancies, making it a promising target for Cancer treatment. Building on our previous work, we report a novel series of tetrahydro-β-carboline-piperazinedione derivatives as HDAC6 inhibitors. Structural modifications were introduced at the 6-aryl group, with the m-bromophenyl derivative (9c) emerging as the most potent HDAC6 Inhibitor, exhibiting an IC50 of 7 nM. Compound 9c demonstrated robust growth inhibitory activity across 60 Cancer cell lines from the NCI panel, with a mean GI50 of 2.64 μM and a GI50 below 5 μM for nearly all tested lines, while exhibiting significantly lower cytotoxicity towards non-tumor cell lines. The triple-negative breast Cancer cell line MDA-MB-231 was selected for further investigation of 9c's cellular effects. 9c selectively increased the acetylation of non-histone α-tubulin in MDA-MB-231 cells, confirming its HDAC6 selectivity. Furthermore, 9c effectively induced Apoptosis, caused apoptotic sub-G1 phase accumulation, upregulated pro-apoptotic Caspase-3, and downregulated anti-apoptotic Bcl-2. Notably, 9c reduced the expression of programmed death-ligand 1 (PD-L1), a key immune checkpoint protein that enables tumor cells to evade immune surveillance, highlighting its potential role in enhancing anti-tumor immunity. In addition, 9c inhibited phosphorylated extracellular signal-regulated kinase (ERK)1/2, a central signaling pathway that drives cell proliferation, survival, and migration, further highlighting its significance in suppressing tumor progression and growth. In migration assays, 9c impaired cell motility, achieving 80% gap closure inhibition in a wound-healing assay. Collectively, these findings underline compound 9c as a highly promising candidate for the treatment of triple-negative breast Cancer, with the added benefits of PD-L1 and ERK inhibition for potential synergy in enhancing anti-tumor immunity and reducing tumor cell proliferation.

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